The coronavirus disease‐2019 (COVID‐19) pandemic caused by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) has already resulted in a huge setback to mankind in terms of millions of deaths, while the unavailability of an appropriate therapeutic strategy has made the scenario much more severe. Toll‐like receptors (TLRs) are crucial mediators and regulators of host immunity and the role of human cell surface TLRs in SARS‐CoV‐2 induced inflammatory pathogenesis has been demonstrated recently. However, the functional significance of the human intracellular TLRs including TLR3, 7, 8, and 9 is yet unclear. Hitherto, the involvement of these intracellular TLRs in inducing pro‐inflammatory responses in COVID‐19 has been reported but the identity of the interacting viral RNA molecule(s) and the corresponding TLRs have not been explored. This study hopes to rationalize the comparative binding of the major SARS‐CoV‐2 mRNAs to the intracellular TLRs, considering the solvent‐based force‐fields operational in the cytosolic aqueous microenvironment that predominantly drives these interactions. Our in silico study on the binding of all mRNAs with the intracellular TLRs depicts that the mRNA of NSP10, S2, and E proteins of SARS‐CoV‐2 are possible virus‐associated molecular patterns that bind to TLR3, TLR9, and TLR7, respectively, and trigger downstream cascade reactions. Intriguingly, binding of the viral mRNAs resulted in variable degrees of conformational changes in the ligand‐binding domain of the TLRs ratifying the activation of the downstream inflammatory signaling cascade. Taken together, the current study is the maiden report to describe the role of TLR3, 7, and 9 in COVID‐19 immunobiology and these could serve as useful targets for the conception of a therapeutic strategy against the pandemic.

中文翻译：

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在计算机上分析人类细胞内TLR对SARS-CoV-2 mRNA的比较感应

由严重急性呼吸系统综合症冠状病毒2（SARS-CoV-2）引起的冠状病毒病-2019（COVID-19）大流行已经导致数百万人死亡，但没有适当的治疗方法策略使情况变得更加严峻。Toll样受体（TLR）是宿主免疫力的重要调节剂和调节剂，最近已证明人细胞表面TLR在SARS-CoV-2诱导的炎症发病机制中的作用。但是，包括TLR3、7、8和9在内的人类细胞内TLR的功能意义尚不清楚。迄今为止，已经报道了这些细胞内TLR参与诱导COVID-19中的促炎反应，但尚未探索相互作用的病毒RNA分子和相应TLR的身份。这项研究希望合理考虑主要SARS-CoV-2 mRNA与细胞内TLR的比较结合，考虑到在胞浆水微环境中主要驱动这些相互作用的基于溶剂的力场。我们对所有mRNA与细胞内TLR结合的计算机研究表明，SARS-CoV-2的NSP10，S2和E蛋白的mRNA是可能与病毒相关的分子模式，分别与TLR3，TLR9和TLR7结合，并触发下游级联反应。有趣的是，病毒mRNA的结合导致TLR配体结合结构域的构象变化程度不同，从而批准了下游炎症信号级联反应的激活。综上所述，本研究是描述TLR3、7的作用的处女报告。